Adoptive T-cell therapy is a promising new technique in which T cells are collected from a cancer patient, genetically engineered to express chimeric antigen receptors specifically directed towards antigens on the patient's tumor cells, and are then infused back into the patient. Unfortunately, the approach requires laborious cloning of antigen-specific T cells or the genetic engineering of autologous T cells from each individual patient and is limited to antigens for which patient-specific T cells can be detected, as well as the need to match T-cell specificity to the human leukocyte antigen (HLA) of the recipient patient in cases of orthologous grafts. A facile platform to produce large quantities of antigen-specific T lymphocytes thus represents an unmet need. Production of T lymphocytes from human induced pluripotent stem cells (iPSCs) in vitro is feasible, offering the potential for such scaled-up production.

In the present work, Themeli and colleagues* combine the aspect of unlimited availability of iPSCs with the ability to custom-tailor the specificity of a T cell through the chimeric antigen receptor technology to generate phenotypically defined, functional, and expandable T cells that are genetically targeted to a tumor antigen of interest (Figures A–F). Peripheral blood T lymphocytes from a healthy volunteer were transduced with two retroviral vectors each encoding two of the reprogramming factors KLF4, SOX2, OCT-4, and c-MYC to produce T-cell iPSCs. An iPSC clone was then stably transduced with a bicistronic lentiviral vector encoding a second-generation chimeric antigen receptor specific for CD19, along with an mCherry fluorescent marker.

The authors found that the generated T cells have the requisite properties of γδ T cells; moreover, the iPSC-derived T cells suppressed tumor growth in a mouse model in which animals were inoculated with human Burkitt lymphoma cells. Thus, the combined use of iPSCs and chimeric antigen receptor technologies can potentially deliver large quantities of T lymphocytes targeted to a chosen antigen.

Overall, the above approach appears to be promising, but as with all types of gene manipulations, the risk of insertional mutagenesis associated with the chimeric antigen receptor engraftment will need to be evaluated extensively.

These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate γδ T cells. Similar to CAR-transduced, peripheral blood γδ T cells, the iPSC–derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells “in the dish” may be useful for cancer immunotherapy and other medical applications.

Anton Simeonov, Ph.D., works at the NIH.

ASSAY & Drug Development Technologies, published by Mary Ann Liebert, Inc., offers a unique combination of original research and reports on the techniques and tools being used in cutting-edge drug development. The journal includes a "Literature Search and Review" column that identifies published papers of note and discusses their importance. GEN presents here one article that was analyzed in the "Literature Search and Review" column, a paper published in Nature Biotechnology titled "Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy." Authors of the paper are Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M, and Sadelain M.

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.

Be sure to take the GEN Poll

Climate Change

How would you describe the researchers response to the 2°C global temperature target?

They are right on the mark. A 2°C global temperature rise will push us further over the edge. We have to set a lower target.

A 2°C global temperature rise is a reasonable target on which to focus in order to diminish the impact of climate change.

We have already gone beyond the threshold for getting a handle on climate change. So now we just need to learn how to adapt to the inexorable climatic changes with which we will have to deal going forward.

They are right on the mark. A 2°C global temperature rise will push us further over the edge. We have to set a lower target.

38.9%

A 2°C global temperature rise is a reasonable target on which to focus in order to diminish the impact of climate change.

22.2%

We have already gone beyond the threshold for getting a handle on climate change. So now we just need to learn how to adapt to the inexorable climatic changes with which we will have to deal going forward.

If you have any questions about your subscription, click
hereto email us or call at (914) 740-2189.

You may also be interested in subscribing to the GEN magazine, an indispensable
resource for everyone involved in the business of translating discoveries at the
bench into solutions that fight disease and improve health, agriculture, and the
environment. Subscribe
today to see why over 60,000 biotech professionals read GEN to
keep current in the areas of genomics, proteomics, drug discovery, biomarker discovery,
bioprocessing, molecular diagnostics, collaborations, biotech business trends, and
more.